Role of TGF-β1, Extracellular Matrix, and Matrix Metalloproteinase in the Healing Process of the Pancreas After Induction of Acute Necrotizing Pancreatitis Using Arginine in Rats

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Abstract
Introduction Pancreatic tissues are almost completely restored to normal after an attack of acute pancreatitis, once the cause of the disease is removed. Transforming growth factor (TGF)-β and extracellular matrix (ECM) are known to play an important role in the process of wound healing in pathologic diseases. Tissue repair is a process regulated by a balance between synthesis and degradation of ECM. Aims To elucidate the role of TGF-β, ECM, and matrix metalloproteinase (MMP) in the process of regeneration occurring after acute necrotizing pancreatitis. Methodology Acute necrotizing pancreatitis was induced by intraperitoneal injection of 500 mg/100 g body weight of L-arginine in male Wistar rats. Expression of TGF-β1 and ECM messenger RNA (mRNA) was determined by Northern blot analysis, and that of MMP-1 and MMP-2 mRNA was examined by the reverse transcription polymerase chain reaction (RT-PCR). Immunoreactivity for ECM components, TGF-β1, and MMP-2 in the pancreas was assessed by using a monoclonal antibody. Results TGF-β1 mRNA expression reached a peak value on day 2.5, with a decrease on day 3, and reached the control level on day 7. Procollagen types III and IV and fibronectin mRNA reached a peak value on day 2.5, whereas the expression level of procollagen type I mRNA was maximal on day 3, and gradually decreased to control levels by day 7. MMP-2 mRNA was significantly elevated on day 3, and peaked on day 5, whereas MMP-1 mRNA levels did not change throughout the observation period. Immunoreactivity for MMP-2 was observed around disrupted acinar cells and interstitial spaces on day 3, and maximally on day 7. Immunoreactivity for fibronectin was detected around disrupted acinar cells and interstitial spaces. On day 7, it was less than on day 5 around disrupted acinar cells and interstitial spaces, whereas in the regenerated acinar cells, it was undetected. Conclusion Our results show that TGF-β1 mRNA expression peaked earlier than that of ECM mRNA. Furthermore, increased level of the MMP-2 transcript was followed by disappearance of fibronectin. Our findings suggest that TGF-β1 plays an important role in ECM production in the early phase of acute pancreatitis, and that MMP-2 is involved in the subsequent healing process.